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Idiopathic pulmonary fibrosis (IPF) is a fatal disease characterized by unpredictable progression and limited therapeutic options. Current diagnosis relies on high resolution computed tomography (HRCT), which may not adequately capture early signs of deterioration. The enzyme autotaxin (ATX) emerges as a prominently expressed extracellular secretory enzyme in the lungs of IPF patients. The objective of this study was to evaluate the effectiveness of 18F-labeled ATX-targeted tracer [18F]ATX-1905, in comparison with [18F]FDG, for early fibrosis diagnosis, disease evolution monitoring, and treatment efficacy assessment in bleomycin-induced pulmonary fibrosis (BPF) models. To assess treatment efficacy, mice were treated with two commonly used drugs for IPF, pirfenidone or nintedanib, from Day 9 to Day 23 postbleomycin administration. Lung tissue assessments encompassed inflammation severity via H&E staining, and Ashcroft scoring via Masson staining, alongside quantification of ATX expression through ELISA. Positron emission tomography (PET) imaging employing [18F]FDG and [18F]ATX-1905 tracked disease progression pre- and post-treatment. The extent of pulmonary fibrosis corresponded to changes in ATX expression levels in the BPF mouse model. Notably, [18F]ATX-1905 exhibited elevated uptake in BPF lungs during the progression of the disease, particularly evident at the early stage (Day 9). This uptake was inhibited by an ATX inhibitor, PF-8380, underscoring the specificity of the radiotracer. Conversely, [18F]FDG uptake, peaking at Day 15, decreased subsequently, likely reflective of diminished inflammation. A 2-week treatment regimen using either pirfenidone or nintedanib resulted in notable reductions of ATX expression levels and fibrosis degrees within lung tissues, based on ELISA and Masson staining, as evidenced by PET imaging with [18F]ATX-1905. [18F]FDG uptake also decreased following the treatment period. Additionally, PET/CT imaging extended to a nonhuman primate (NHP) BPF model. The uptake of [18F]ATX-1905 (SUVmax = 2.2) was significantly higher than that of [18F]FDG (SUVmax = 0.7) in fibrotic lung tissue. Using our novel ATX-specific radiotracer [18F]ATX-1905 and PET/CT imaging, we demonstrated excellent ability in early fibrosis detection, disease monitoring, and treatment assessment within lungs of the BPF mouse models. [18F]ATX-1905 displayed remarkable specificity for ATX expression and high sensitivity for ATX alterations, suggesting its potential for monitoring varying ATX expression in lungs of IPF patients.
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The metabotropic glutamate receptor 2 (mGluR2) has emerged as a potential therapeutic target for the treatment of various neurological diseases, prompting substantial interest in the development of mGluR2-targeted drug candidates. As part of our medicinal chemistry program, we synthesized a series of isoindolone derivatives and assessed their potential as mGluR2 positive allosteric modulators (PAMs). Notably, AZ12559322 exhibited high affinity (K i mGluR2 = 1.31 nM) and an excellent in vitro binding specificity of 89% while demonstrating selectivity over other mGluR subtypes (>4000-fold). Autoradiography with the radiolabeled counterpart, [3H]AZ12559322, revealed a heterogeneous accumulation with the highest binding in mGluR2-rich brain regions. Radioligand binding was significantly reduced by pretreatment with nonradioactive mGluR2 PAMs in brains of rats and nonhuman primates. Although positron emission tomography imaging of [11C]AZ12559322 (6a) revealed low brain uptake in a nonhuman primate, this study provides valuable guidance to further design novel isoindolone-based mGluR2 PAMs with improved brain exposure.
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The synergistic treatment of oily wastewater containing organic hazards and emulsified oils remains a big challenge for membrane separation technology. Herein, the photocatalytic membrane, which combined the physical barrier and catalytic oxidation-driven degradation functionality, was fabricated via anchoring a nanoflower-branched CoAl-LDH@PANI Z-scheme heterojunction onto a porous polyacrylonitrile mat and using tannic acid as an adhesive. The assembly of such a Z-scheme heterojunction offered the superior photocatalytic degradation performance of soluble dyes and tetracycline (up to 94.3%) to the membrane with the improved photocatalytic activity of 2.33 times compared with the CoAl-LDH@pPAN membrane. Quenching experiments suggested that the â¢O2- was the most reactive oxygen species in the catalytic reaction system of the composite membrane. The greatly enhanced photocatalytic activity was attributed to the effective inhibition of photogenerated hole-electron combination using PANI as a carrier, with charge transferring from LDH to PANI. The possible photocatalytic degradation mechanism was proposed based on VB-XPS, electron spin resonance spectroscopy, and DRS technologies, which was confirmed by density functional theory calculation. Meanwhile, benefiting from the superhydrophilic/oleophobic feature and low oil adhesion, the membrane exhibited high permeability for isooctane emulsion (3990.39 L·m-2·h-1), high structure stability, and satisfactory cycling performance. This work provided a strategy to develop superwetting and photocatalytic composite membranes for treating complex multicomponent pollutants in the chemical industry.
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BACKGROUND: Oncomelania hupensis is the exclusive intermediate host of Schistosoma japonicum in China. Snail control is an essential component of schistosomiasis elimination programme. With 70 years of continuous efforts, the range of O. hupensis had reduced significantly, but slowed down in last decades. A large number of levees against flooding were constructed along Yangtze River and its affiliated lakes in the middle and lower reaches, which influenced the hydrology and ecology in the alluvial plains. The purpose of this study was to assess the impact of levees on the distribution of O. hupensis in the middle and lower reaches of the Yangtze River. METHODS: The snail habitats were digitalised by hand-held GPS system. The years for discovery and elimination of snail habitats were extracted from historical records. The accumulated snail-infested range for each habitat was calculated on the basis of annual reports. The current distribution of O. hupensis was determined by systematic and environmental sampling. The geographical distribution of levees was obtained from satellite imagery. To assess the impact of levees, the data pertaining to O. hupensis were divided into two parts: inside and outside the Yangtze River. Joinpoint regression was utilised to divide the study time span and further characterise the regression in each period. The 5-year-period moving averages of eliminated area infested by snails were calculated for the habitats inside and outside Yangtze River. The moving routes of corresponding geographical median centres were simulated in ArcGIS. Hotspot analysis was used to determine the areas with statistical significance clustering of O. hupensis density. RESULTS: Three periods were identified according to Joinpoint regression both inside and outside Yangtze River. The area infested by O. hupensis increased in the first two periods. It decreased rapidly outside Yangtze River year over year after 1970, while that inside the Yangtze River did not change significantly. Furthermore, the latter was significantly higher than the former. It was observed that the present density of O. hupensis inside Yangtze River was lower than outside the Yangtze River. The median centre for eliminated ranges inside Yangtze River wavered between the east (lower reach) and the west (middle reach). In contrast, the median centre for eliminated ranges continuously moved from the east to the west. CONCLUSIONS: Our findings indicated that the levees had a considerable negative impact on the distribution of O. hupensis outside Yangtze River. Some hotspots observed in the irrigation areas need a sluice system at the inlet of branch for snail control. The major distribution of O. hupensis located in Hubei might be caused by severe waterlogging. The intensive surveillance should be implemented there. The biggest two freshwater lakes, the major endemic regions historically, were identified as cold spots. The long-term impact of Three Gorges Dam on the distribution of O. hupensis in the lakes should be monitored and evaluated.
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Ecossistema , Rios , Schistosoma japonicum , Caramujos , Animais , Caramujos/parasitologia , Rios/parasitologia , China , Schistosoma japonicum/fisiologia , Esquistossomose Japônica/transmissão , Esquistossomose Japônica/epidemiologia , Esquistossomose Japônica/parasitologiaRESUMO
The strategic installation of a [18F]fluorine atom at the specific position of the lead molecule is a never-ending challenge for radiochemists in their endeavour to develop novel positron emission tomography (PET) imaging applications. Although the radiosynthesis of [18F]CF2H-containing molecules has been explored in the past decade, more methods need to be explored for various well-functionalized compounds. Recently, two novel strategies of radiodifluoromethylation were reported, namely the utilization of [18F]difluorocarbene building block and frustrated Lewis pair-mediated C-18F bond formation, respectively. These methods provide an efficient radiofunctionalization of complex CF2H-containing molecules for drug discovery and PET ligand development.
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OBJECTIVES: This qualitative study aimed to explore opportunities to strengthen tuberculosis (TB) health service delivery from the perspectives of health workers providing TB care in Shigatse prefecture of Tibet Autonomous Region, China. DESIGN: Qualitative research, semi-structured in-depth interviews. SETTING: The TB care ecosystem in Shigatse, including primary and community care. PARTICIPANTS: Participants: 37 semi-structured interviews were conducted with village doctors (14), township doctors and nurses (14), county hospital doctors (7) and Shigatse Centre for Disease Control staff (2). RESULTS: The three main themes reported include (1) the importance of training primary and community health workers to identify people with symptoms of TB, ensure TB is diagnosed and link people with TB to further care; (2) the need to engage community health workers to ensure retention in care and adherence to TB medications; and (3) the opportunity for innovative technologies to support coordinated care, retention in care and adherence to medication in Shigatse. CONCLUSIONS: The quality of TB care could be improved across the care cascade in Tibet and other high-burden, remote settings by strengthening primary care through ongoing training, greater support and inclusion of community health workers and by leveraging technology to create a circle of care. Future formative and implementation research should include the perspectives of health workers at all levels to improve care organisation and delivery.
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Agentes Comunitários de Saúde , Pesquisa Qualitativa , Serviços de Saúde Rural , Tuberculose , Humanos , Tibet , Tuberculose/terapia , Tuberculose/prevenção & controle , Serviços de Saúde Rural/organização & administração , Agentes Comunitários de Saúde/educação , Feminino , Masculino , Entrevistas como Assunto , Adulto , Pessoal de Saúde/educação , Atenção à Saúde/organização & administração , Atenção Primária à Saúde/organização & administração , Atenção Primária à Saúde/métodos , Pessoa de Meia-IdadeRESUMO
Chiral spiro-polycyclic oxindoles are valuable heterocyclic ring systems that are widely distributed in natural alkaloids and biologically active compounds. Herein, we reported an asymmetric tandem Michael addition/interrupted Nef reaction of nitromethane with oxindole-derived alkenes catalyzed by a chiral 2-aminobenzimidazole bifunctional organocatalyst. A series of novel enantiomerically enriched spiro-polycyclic oxindole derivatives bearing an oxime group were synthesized in moderate to excellent isolated yields (up to 99%) with an excellent level of enantioselectivities (up to 99% ee). Furthermore, the antiproliferation activity of the resulting oxindoles derivatives were evaluated, and compound 2d demonstrated promising anticancer properties against HCT116 (IC50 = 14.08 µM) and HT29 (IC50 = 15.46 µM) cell lines.
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BACKGROUND: WHO recommends that electronic medication monitors, a form of digital adherence technology, be used as a complement to directly observed treatment (DOT) for tuberculosis, as DOT is inconvenient and costly. However, existing evidence about the effectiveness of these monitors is inconclusive. Therefore, we evaluated the effectiveness of a comprehensive package based on electronic medication monitors among patients with tuberculosis in Tibet Autonomous Region (hereafter Tibet), China. METHODS: This multicentre, randomised controlled trial recruited patients from six counties in Shigatse, Tibet. Eligible participants had drug-susceptible tuberculosis and were aged 15 years or older when starting standard tuberculosis treatment. Tuberculosis doctors recruited patients from the public tuberculosis dispensary in each county and the study statistician randomly assigned them to the intervention or control group based on the predetermined randomised allocation sequence. Intervention patients received an electronic medication monitor box. The box included audio medication-adherence reminders and recorded box-opening data, which were transmitted to a cloud-based server and were accessible to health-care providers to allow remote adherence monitoring. A linked smartphone app enabled text, audio, and video communication between patients and health-care providers. Patients were also provided with a free data plan. Patients selected a treatment supporter (often a family member) who was trained to support patients with using the electronic medication monitor and app. Patients in the control group received usual care plus a deactivated electronic medication monitor, which only recorded and transmitted box-opening data that was not made available to health-care providers. The control group also had no access to the app or trained treatment supporters. The primary outcome was a binary indicator of poor monthly adherence, defined as missing 20% or more of planned doses in the treatment month, measured using electronic medication monitor opening data, and verified by counting used medication blister packages during consultations. We recorded other secondary treatment outcomes based on national tuberculosis reporting data. We analysed the primary outcome based on the intention-to-treat population. This trial is registered at ISRCTN, 52132803. FINDINGS: Between Nov 17, 2018, and April 5, 2021, 278 patients were enrolled into the study. 143 patients were randomly assigned to the intervention group and 135 patients to the control group. Follow-up ended when the final patient completed treatment on Oct 4, 2021. In the intervention group, 87 (10%) of the 854 treatment months showed poor adherence compared with 290 (37%) of the 795 months in the control group. The corresponding adjusted risk difference for the intervention versus control was -29·2 percentage points (95% CI -35·3 to -22·2; p<0·0001). Five of the six secondary treatment outcomes also showed clear improvements, including treatment success, which was found for 133 (94%) of the 142 individuals in the intervention arm and 98 (73%) of the 134 individuals in the control arm, with an adjusted risk difference of 21 percentage points (95% CI 12·4-29·4); p<0·0001. INTERPRETATION: The interventions were effective at improving tuberculosis treatment adherence and outcomes, and the trial suggests that a comprehensive package involving electronic medication monitors might positively affect tuberculosis programmes in high-burden and low-resource settings. FUNDING: TB REACH.
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Tuberculose , Humanos , Tibet , Tuberculose/tratamento farmacológico , Resultado do Tratamento , Adesão à Medicação , ChinaRESUMO
Parkinson's disease (PD) is one of the most highly debilitating neurodegenerative disorders, which affects millions of people worldwide, and leucine-rich repeat kinase 2 (LRRK2) mutations have been involved in the pathogenesis of PD. Developing a potent LRRK2 positron emission tomography (PET) tracer would allow for in vivo visualization of LRRK2 distribution and expression in PD patients. In this work, we present the facile synthesis of two potent and selective LRRK2 radioligands [11C]3 ([11C]PF-06447475) and [18F]4 ([18F]PF-06455943). Both radioligands exhibited favorable brain uptake and specific bindings in rodent autoradiography and PET imaging studies. More importantly, [18F]4 demonstrated significantly higher brain uptake in the transgenic LRRK2-G2019S mutant and lipopolysaccharide (LPS)-injected mouse models. This work may serve as a roadmap for the future design of potent LRRK2 PET tracers.
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Morfolinas , Nitrilas , Doença de Parkinson , Pirimidinas , Camundongos , Animais , Humanos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/metabolismo , Leucina , Tomografia por Emissão de Pósitrons/métodos , Doença de Parkinson/metabolismo , MutaçãoRESUMO
AMPA glutamate receptors (AMPARs) play a pivotal role in excitatory neurotransmission, particularly in the hippocampus where the TARP γ-8 subunit is enriched and serves as a target for emerging anti-epileptic drugs. To enable inâ vivo visualization of TARP γ-8 distribution and expression by positron emission tomography (PET), this study focuses on the development of novel 18 F-labeled TARP γ-8 inhibitors and their corresponding precursors, stemming from the azabenzimidazole scaffold. The resulting radioligands [18 F]TARP-2204 and [18 F]TARP-2205 were successfully synthesized with acceptable radiochemical yield, high molar activity, and excellent radiochemical purity. In vitro autoradiography demonstrates high level of specific binding of [18 F]TARP-2205 to TARP γ-8 in both rat and nonhuman primate brain tissues. However, unexpected radiodefluorination in PET imaging studies of rodents emphasizes the need for further structural refinement. This work serves as an excellent starting point for the development of future 18 F-labeled TARP γ-8 PET tracers, offering valuable insights into medicinal chemistry design, radiosynthesis and subsequent PET evaluation.
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Tomografia por Emissão de Pósitrons , Receptores de AMPA , Ratos , Animais , Receptores de AMPA/metabolismo , Tomografia por Emissão de Pósitrons/métodos , HipocampoRESUMO
In this research, a recombinant Bacillus Calmette Guerin (rBCG) vector vaccine carrying a human IL-2 and EBV BZLF1 fusion gene (IL-2-BZLF1-rBCG) was constructed. The IL-2-BZLF1-rBCG construct was successfully generated and stably expressed the IL-2 and BZLF1 proteins. IL-2-BZLF1-rBCG activated the immune system and promoted the secretion of IFN-γ and TNF-α by CD4+ and CD8+ T cells. IL-2-BZLF1-rBCG activated lymphocytes to effectively kill EBV-positive NPC cells in vitro. Additionally, IL-2-BZLF1-rBCG stimulated the proliferation of NK cells and lymphocytes in vivo, activated related immune responses, and effectively treated EBV-positive NPC. The immune response to and pharmacological effect of IL-2-BZLF1-rBCG were explored in vitro and in vivo to provide a theoretical and experimental basis for the prevention and treatment of EBV-positive tumors with an rBCG vector vaccine. KEY POINTS: ⢠rBCG with human IL-2 and BZLF1 of EB virus was constructed ⢠The IL-2-BZLF1 fusion gene was stably expressed with rBCG ⢠rBCG with IL-2-BZLF1 has an obvious immune response in vitro and in vivo.
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Mycobacterium bovis , Neoplasias , Humanos , Interleucina-2/genética , Linfócitos T CD8-Positivos , Mycobacterium bovis/genética , Vacina BCG , Transativadores/genéticaRESUMO
OBJECTIVE: Precision interventions have been proposed in transmission-interrupted areas to further reduce the potential transmission risk of schistosomiasis. This study aimed to evaluate the effects of different interventions modes for potential transmission risk control. METHODS: Three groups of schistosomiasis-endemic villages were selected in Jiangling county, Hubei province. After baseline surveys in 2020, three intervention models were employed in 2021 and 2022. In Model 1, Oncomelania hupensis snail control in key settings and an integrated strategy with an emphasis on the infectious sources managing was employed. In Model 2, an integrated health education-led strategy with an emphasis on infectious source management was employed. In Model 3, only the integrated strategy with an emphasis on infectious source management was employed. The effects of the different intervention models were examined with multiple indicators after 2 years of intervention using the entropy-weighted technique for order of preference by similarity to ideal solution (TOPSIS), rank-sum ratio (RSR) and fuzzy combination model of entropy-weighted TOPSIS and RSR. RESULTS: Entropy-weighted TOPSIS modeling showed that the Ci values of Model 2 were 0.4434, 0.2759, and 0.3069 in the three pilot villages, Ci values were larger, with top comprehensive ranking. The results of the RSR method showed that the RSR values of Model 2 were 0.75, 0.708, and 0.736 in the three pilot villages, with top comprehensive ranking. The results from the fuzzy combination model of entropy-weighted TOPSIS and RSR showed that implementation of Model 2 resulted in the highest comprehensive ranking among the three models in the three pilot villages under Ci: RSR = 0.1: 0.9, Ci: RSR = 0.5: 0.5 and Ci: RSR = 0.9: 0.1. CONCLUSION: The integrated health education-led strategy with an emphasis on infectious source management was the optimal model to manage the risk of transmission of schistosomiasis during the post-transmission interruption phase.
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Esquistossomose , Animais , Humanos , Esquistossomose/epidemiologia , Esquistossomose/prevenção & controle , Caramujos , Educação em Saúde , Inquéritos e Questionários , China/epidemiologiaRESUMO
As a subclass of ionotropic glutamate receptors (iGluRs), α-amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid (AMPA) receptors have been implicated in various neurological disorders and neurodegenerative diseases. To further our understanding of AMPA receptor-related disorders in the central nervous system (CNS), it is important to be able to image and quantify AMPA receptors in vivo. In this study, we identified a novel F-containing AMPA positive allosteric modulator (PAM) 6 as a potential lead compound. Molecular docking studies and CNS PET multi-parameter optimization (MPO) analysis were used to predict the absorption, distribution, metabolism, and excretion (ADME) characteristics of 6 as a PET probe. The resulting PET probe, [18F]6 (codename [18F]AMPA-2109), was successfully radiolabeled and demonstrated excellent blood-brain barrier (BBB) permeability and high brain uptake in rodents and non-human primates. However, [18F]6 did not show substantial specific binding in the rodent or non-human primate brain. Further medicinal chemistry efforts are necessary to improve specific binding, and our work may serve as a starting point for the design of novel 18F-labeled AMPA receptor-targeted PET radioligands aimed for clinical translation.
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Receptores de AMPA , Tiadiazinas , Animais , Receptores de AMPA/metabolismo , Tiadiazinas/metabolismo , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico , Simulação de Acoplamento Molecular , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Roedores/metabolismoRESUMO
GluN2B subunit-containing N-methyl-d-aspartate (NMDA) receptors have been implicated in various neurological disorders. Nonetheless, a validated fluorine-18 labeled positron emission tomography (PET) ligand for GluN2B imaging in the living human brain is currently lacking. The aim of this study was to develop a novel synthetic approach that allows an enantiomerically pure radiosynthesis of the previously reported PET radioligands (R)-[18F]OF-NB1 and (S)-[18F]OF-NB1 as well as to assess their in vitro and in vivo performance characteristics for imaging the GluN2B subunit-containing NMDA receptor in rodents. A novel synthetic approach was successfully developed, which allows for the enantiomerically pure radiosynthesis of (R)-[18F]OF-NB1 and (S)-[18F]OF-NB1 and the translation of the probe to the clinic. While both enantiomers were selective over sigma2 receptors in vitro and in vivo, (R)-[18F]OF-NB1 showed superior GluN2B subunit specificity by in vitro autoradiography and higher volumes of distribution in the rodent brain by small animal PET studies.
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Tomografia por Emissão de Pósitrons , Receptores de N-Metil-D-Aspartato , Animais , Humanos , Receptores de N-Metil-D-Aspartato/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Radioisótopos de FlúorRESUMO
The cannabinoid type 2 receptor (CB2) has been implicated in a variety of central and peripheral inflammatory diseases, prompting significant interest in the development of CB2-targeted diagnostic and therapeutic agents. A validated positron emission tomography (PET) radioligand for imaging CB2 in the living human brain as well as in peripheral tissues is currently lacking. As part of our research program, we have recently identified the trisubstituted pyridine, [18F]RoSMA-18-d6, which proved to be highly suitable for in vitro and in vivo mapping of CB2 in rodents. The aim of this study was to assess the performance characteristics of [18F]RoSMA-18-d6 in nonhuman primates (NHPs) to pave the way for clinical translation. [18F]RoSMA-18-d6 was synthesized from the respective tosylate precursor according to previously reported procedures. In vitro autoradiograms with NHP spleen tissue sections revealed a high binding of [18F]RoSMA-18-d6 to the CB2-rich NHP spleen, which was significantly blocked by coincubation with the commercially available CB2 ligand, GW405833 (10 µM). In contrast, no specific binding was observed by in vitro autoradiography with NHP brain sections, which was in agreement with the notion of a CB2-deficient healthy mammalian brain. In vitro findings were corroborated by PET imaging experiments in NHPs, where [18F]RoSMA-18-d6 uptake in the spleen was dose-dependently attenuated with 1 and 5 mg/kg GW405833, while no specific brain signal was observed. Remarkably, we observed tracer uptake and retention in the NHP spinal cord, which was reduced by GW405833 blockade, pointing toward a potential utility of [18F]RoSMA-18-d6 in probing CB2-expressing cells in the bone marrow. If these observations are substantiated in NHP models of enhanced leukocyte proliferation in the bone marrow, [18F]RoSMA-18-d6 may serve as a valuable marker for hematopoietic activity in various pathologies. In conclusion, [18F]RoSMA-18-d6 proved to be a suitable PET radioligand for imaging CB2 in NHPs, supporting its translation to humans.
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Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Animais , Humanos , Compostos Radiofarmacêuticos/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Ligantes , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Primatas/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Radioisótopos de Flúor/metabolismo , Mamíferos/metabolismoRESUMO
Orexin 2 receptors (OX2R) represent a vital subtype of orexin receptors intricately involved in the regulation of wakefulness, arousal, and sleep-wake cycles. Despite their importance, there are currently no positron emission tomography (PET) tracers available for imaging the OX2R in vivo. Herein, we report [11C]1 ([11C]OX2-2201) and [11C]2 ([11C]OX2-2202) as novel PET ligands. Both compounds 1 (Ki = 3.6 nM) and 2 (Ki = 2.2 nM) have excellent binding affinity activities toward OX2R and target selectivity (OX2/OX1 > 600 folds). In vitro autoradiography in the rat brain suggested good to excellent in vitro binding specificity for [11C]1 and [11C]2. PET imaging in rat brains indicated that the low brain uptake of [11C]2 may be due to P-glycoprotein and/or breast cancer resistance protein efflux interaction and/or low passive permeability. Continuous effort in medicinal chemistry optimization is necessary to improve the brain permeability of this scaffold.
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OBJECTIVES: Previous studies have found an association between socioeconomic status (SES) and depressive symptoms among older adults, however the mechanisms underlying this association remained unclear. This study aimed to examine the mediating role of social support and the moderating role of living arrangement in the association between SES and depressive symptoms. METHODS: Data was collected from the 2020 Household Health Interview Survey in Taian city, Shandong Province, China. A total of 3896 older adults aged 60 and above were included in this study. Depressive symptoms was measured by the Patient health Questionnaire-9 (PHQ-9), Social support by the Multidimensional Scale of Perceived Social Support (MSPSS), and other variables by related demographic scales. The moderated mediation model was examined using HAYES PROCESS 3.5. RESULTS: SES negatively predicted depressive symptoms among older adults, and social support could mediate this association. Living arrangement played a moderating role in the relationship between social support and depressive symptoms (the second half of the mediating effect), and the effect was stronger among older adults who lived alone. CONCLUSIONS: Social support partially mediated the relationship between SES and depressive symptoms among older adults, and living alone strengthened the effect of social support on depressive symptoms. Interventions that address older adults' social support and living arrangement may ameliorate depressive symptoms among older adults.
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Depressão , Classe Social , Humanos , Idoso , Depressão/epidemiologia , Apoio Social , China/epidemiologia , Inquéritos EpidemiológicosRESUMO
Cholinergic receptors represent a promising class of diagnostic and therapeutic targets due to their significant involvement in cognitive decline associated with neurological disorders and neurodegenerative diseases as well as cardiovascular impairment. Positron emission tomography (PET) is a noninvasive molecular imaging tool that has helped to shed light on the roles these receptors play in disease development and their diverse functions throughout the central nervous system (CNS). In recent years, there has been a notable advancement in the development of PET probes targeting cholinergic receptors. The purpose of this review is to provide a comprehensive overview of the recent progress in the development of these PET probes for cholinergic receptors with a specific focus on ligand structure, radiochemistry, and pharmacology as well as in vivo performance and applications in neuroimaging. The review covers the structural design, pharmacological properties, radiosynthesis approaches, and preclinical and clinical evaluations of current state-of-the-art PET probes for cholinergic receptors.
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Compostos Radiofarmacêuticos , Receptores Colinérgicos , Compostos Radiofarmacêuticos/química , Tomografia por Emissão de Pósitrons/métodos , Encéfalo/diagnóstico por imagem , Sistema Nervoso CentralRESUMO
N-methyl-D-aspartate receptors (NMDAR), ionotropic glutamate receptors, mediate a slow component of excitatory synaptic transmission in the central nervous system and play a key role in normal brain function and development. Genetic variations in GRIN genes encoding NMDAR subunits that alter the receptor's functional characteristics are associated with a wide range of neurological and neuropsychiatric conditions. Pathological GRIN variants located in the M2 re-entrant loop lining the channel pore cause significant functional changes, the most consequential alteration being a reduction in voltage-dependent Mg2+ inhibition. Voltage-dependent Mg2+ block is a unique feature of NMDAR biology whereby channel activation requires both ligand binding and postsynaptic membrane depolarization. Thus, loss of NMDAR Mg2+ block will have a profound impact on synaptic function and plasticity. Here, we choose 11 missense variants within the GRIN1, GRIN2A, and GRIN2B genes that alter residues located in the M2 loop and significantly reduce Mg2+ inhibition. Each variant was evaluated for tolerance to genetic variation using the 3-dimensional structure and assessed for functional rescue pharmacology via electrophysiological recordings. Three FDA-approved NMDAR drugs-memantine, dextromethorphan, and ketamine-were chosen based on their ability to bind near the M2 re-entrant loop, potentially rectifying dysregulated NMDAR function by supplementing the reduced voltage-dependent Mg2+ block. These results provide insight of structural determinants of FDA-approved NMDAR drugs at their binding sites in the channel pore and may further define conditions necessary for the use of such agents as potential rescue pharmacology.
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The goal of schistosomiasis prevention and control in China is shifting from transmission interruption to elimination. However, the area inhabited by the intermediate host, the snail Oncomelania hupensis, has not changed much in recent years. Different environmental types have different impacts on snail breeding, and understanding these differences is conducive to improving the efficiency of snail monitoring and control and to saving resources. Based on previous epidemiological data, we selected 199 villages in 2020 and 269 villages in 2021 from transmission control, transmission interruption, and elimination areas of snail breeding. Snail surveys were conducted in selected villages using systematic sampling and/or environmental sampling methods in six types of snail-breeding environments (canals, ponds, paddy fields, dry lands, bottomlands, and undefined environments). All live snails collected from the field were evaluated for Schistosoma japonicum infection using the microscopic dissection method, and a subsample of snails was subjected to loop-mediated isothermal amplification (LAMP) to assess the presence of S. japonicum infection. Snail distribution data and infection rate and nucleic acid positive rate of schistosomes in snails were calculated and analyzed. The 2-year survey covered 29,493 ha of the environment, in which 12,313 ha of snail habitats were detected. In total, 51.16 ha of new snail habitats and 107.76 ha of re-emergent snail habitats were identified during the survey. The occurrence rate of snails in canals (10.04%, 95% CI: 9.88-10.20%) and undefined environments (20.66%, 95% CI: 19.64-21.67%) was relatively high in 2020, and the density of snails in bottomlands (0.39, 95% CI: 0.28-0.50) and undefined environments (0.43, 95% CI: 0.14-1.60) was relatively high in 2021. Of the 227,355 live snails collected in this study, none were S. japonicum-positive as determined by microscopy. Of the 20,131 pooled samples, however, 5 were S. japonicum-positive based on LAMP analysis, and they were distributed in three environmental types: 3 in bottomland, 1 in dry land, and 1 in a canal. The bottomland environment has a high risk of schistosomiasis transmission because it contains a large area of newly emerging and re-emerging snail habitats, and it also had the most breeding snails infected with S. japonicum. Thus, this habitat type should be the key target for snail monitoring and early warning and for the prevention and control of schistosomiasis.